Sublingual buccal effervescent

ABSTRACT

A pharmaceutical dosage form adapted to supply a medicament to the oral cavity for buccal, sublingual or gingival absorption of the medicament which contains an orally administrable medicament in combination with an effervescent for use in promoting absorption of the medicament in the oral cavity. The use of an additional pH adjusting substance in combination with the effervescent for promoting the absorption drugs is also disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation application of U.S. patentapplication Ser. No. 10/977,029 filed Oct. 29, 2004, which is acontinuation of U.S. patent application Ser. No. 10/269,669 filed Oct.11, 2002, which is a divisional application of U.S. patent applicationSer. No. 09/661,693, filed Sep. 14, 2000, which is a continuationapplication of U.S. patent application Ser. No. 09/327,814 filed Jun. 8,1999, which is a continuation application of U.S. patent applicationSer. No. 09/277,424, filed Mar. 26, 1999, which claims the benefit ofU.S. Provisional Application No. 60/079,652 filed on Mar. 27, 1998, thebenefit of which is claimed under 35 U.S.C. §120 and the disclosure ofwhich is incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions, and moreparticularly to pharmaceutical compositions for oral administration of amedicament, which contain an effervescent agent for enhancing oral drugabsorption across the buccal, sublingual, and gingival mucosa.

DESCRIPTION OF PRIOR ART

Effervescents have been shown to be useful and advantageous for oraladministration. See Pharmaceutical Dosage Forms: Tablets Volume I,Second Edition. A. Lieberman. ed. 1989, Marcel Dekker, Inc. As discussedin this text, and as commonly employed, an effervescent tablet isdissolved in water to provide a carbonated or sparkling liquid drink.See also U.S. Pat. Nos. 5,102,665 and 5,468,504 to Schaeffer, hereinincorporated by reference. In such a drink, the effervescent helps tomask the taste of medicaments.

Effervescent compositions have also been employed for use as tastemasking agents in dosage forms which are not dissolved in water prior toadministration. For example, U.S. Pat. No. 4,639,368 describes a chewinggum containing a medicament capable of absorption through the buccalcavity and containing a taste masking amount of an effervescent.

More recently effervescents have been employed to obtain rapiddissolution and/or dispersion of the medicament in the oral cavity. SeeU.S. Pat. Nos. 5,178,878 and 5,223,264. The effervescent tends tostimulate saliva production thereby providing additional water to aid infurther effervescent to a faster onset of action and/or improvedbioavailability action. These dosage forms give an agreeablepresentation of the drug, particularly for patients who have difficultyin swallowing tablets or capsules. PCT application WO 97/06786 describespre-gastric absorption of certain drugs using rapidly-disbursing dosageforms.

Various proposals have been advanced for oral mucosal administration ofvarious drugs. When drugs are absorbed from the oral mucosa, they bypassthe gastrointestinal and hepatic metabolism process. This can lead of adrug. However, many compounds do not rapidly penetrate the oral mucosa.See, e.g., Christina Graffner, Clinical Experience with Novel Buccal andSublingual Administration; NOVEL DRUG DELIVERY AND ITS THERAPEUTICAPPLICATION, edited by L. F. Prescott and W. S. Nimmo (1989); DavidHarris & Joseph R. Robinson, Drug Delivery via the Mucous Membranes ofthe Oral Cavity; JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 81 (January1992); Oral Mucosal Delivery, edited by M. J. Rathbone, which are hereinincorporated by reference. The compounds which may be well absorbedper-orally (through the gastrointestinal tract) may not be well absorbedthrough the mucosa of the mouth because the oral mucosa is lesspermeable than the intestinal mucosa and it does not offer as big asurface area as the small intestine.

Despite these and other efforts toward increasing the permeation ofmedicaments across the oral mucosa, there have been unmet needs forimproved methods of administrating medicaments across the oral mucosa.

SUMMARY OF THE INVENTION

The pharmaceutical compositions of the present invention comprise anorally administrable medicament in combination with an effervescentagent used as penetration enhancer to influence the permeability of themedicament across the buccal, sublingual, and gingival mucosa.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of this invention is to use effervescent as penetrationenhancers for influencing oral drug absorption. Effervescent agents canbe used alone or in combination with other penetration enhancers, whichleads to an increase in the rate and extent of absorption of an activedrug. It is believed that such increase can rise from one or all of thefollowing mechanisms:

-   -   1. reducing the mucosal layer thickness and/or viscosity;    -   2. tight junction alteration;    -   3. inducing a change in the cell membrane structure; and    -   4. increasing the hydrophobic environment within the cellular        membrane.

The present dosage forms should include an amount of an effervescentagent effective to aid in penetration of the drug across the oralmucosa. Preferably, the effervescent is provided in an amount of betweenabout 5% and about 95% by weight, based on the weight of the finishedtablet, and more preferably in an amount of between about 30% and about80% by weight. It is particularly preferred that sufficient effervescentmaterial be provided such that the evolved gas is more than about 5 cm³but less than about 30 cm³, upon exposure of the tablet to an aqueousenvironment. However, the amount of effervescent agent must be optimizedfor each specific drug.

The term “effervescent agent” includes compounds which evolve gas. Thepreferred effervescent agents evolve gas by means of a chemical reactionwhich takes place upon exposure of the effervescent agent (aneffervescent couple) to water and/or to saliva in the mouth. Thisreaction is most often the result of the reaction of a soluble acidsource and a source of carbon dioxide such as an alkaline carbonate orbicarbonate. The reaction of these two general compounds produces carbondioxide gas upon contact with water or saliva. Such water-activatedmaterials must be kept in a generally anhydrous state and with little orno absorbed moisture or in a stable hydrated form, since exposure towater will prematurely disintegrate the tablet. The acid sources may beany which are safe for human consumption and may generally include foodacids, acid and hydrite antacids such as, for example: citric, tartaric,amalic, fumeric, adipic, and succinics. Carbonate sources include drysolid carbonate and bicarbonate salt such as, preferably, sodiumbicarbonate, sodium carbonate, potassium bicarbonate and potassiumcarbonate, magnesium carbonate and the like. Reactants which evolveoxygen or other gasses and which are safe for human consumption are alsoincluded.

The effervescent agent(s) of the present invention is not always basedupon a reaction which forms carbon dioxide. Reactants which evolveoxygen or other gasses which are safe for human consumption are alsoconsidered within the scope. Where the effervescent agent includes twomutually reactive components, such as an acid source and a carbonatesource, it is preferred that both components react completely.Therefore, an equivalent ratio of components which provides for equalequivalents is preferred. For example, if the acid used is diprotic,then either twice the amount of a mono-reactive carbonate base, or anequal amount of a di-reactive base should be used for completeneutralization to be realized. However, in other embodiments of thepresent invention, the amount of either acid or carbonate source mayexceed the amount of the other component. This may be useful to enhancetaste and/or performance of a tablet containing an overage of eithercomponent. In this case, it is acceptable that the additional amount ofeither component may remain unreacted.

The present dosage forms may also include in amounts additional to thatrequired for effervescence a pH adjusting substance. For drugs that areweakly acidic or weakly basic, the pH of the aqueous environment caninfluence the relative concentrations of the ionized and unionized formsof the drug present in solution according to the Henderson-Hasselbachequation. The pH solutions in which an effervescent couple has dissolvedis slightly acidic due to the evolution of carbon dioxide. The pH of thelocal environment, e.g., saliva in immediate contact with the tablet andany drug that may have dissolved from it, may be adjusted byincorporating in the tablet a pH adjusting substances which permit therelative portions of the ionized and unionized forms of the drug to becontrolled. In this way, the present dosage forms can be optimized foreach specific drug. If the unionized drug is known or suspected to beabsorbed through the cell membrane (transcellular absorption) it wouldbe preferable to alter the pH of the local environment (within thelimits tolerable to the subject) to a level that favors the unionizedform of the drug. Conversely, if the ionized form is more readilydissolved the local environment should favor ionization.

The aqueous solubility of the drug should preferably not be compromisedby the effervescent and pH adjusting substance, such that the dosageforms permit a sufficient concentration of the drug to be present in theunionized form. The percentage of the pH adjusting substance and/oreffervescent should therefore be adjusted depending on the drug.

Suitable pH adjusting substance for use in the present invention includeany weak acid or weak base in amounts additional to that required forthe effervescence or, preferably, any buffer system that is not harmfulto the oral mucosa. Suitable pH adjusting substance for use in thepresent invention include, but are not limited to, any of the acids orbases previously mentioned as effervescent compounds, disodium hydrogenphosphate, sodium dihydrogen phosphate and the equivalent potassiumsalt.

The active ingredient suitable for use in the present dosage forms caninclude systematically distributable pharmaceutical ingredients,vitamins, minerals, dietary supplements, as well as non-systematicallydistributable drugs. Preferably, the active ingredient is a systemicallyactive pharmaceutical ingredient which is absorbable by the body throughthe oral mucosa. Although the dosage forms can be employed with a widerange of drugs, as discussed below, it is especially suitable for drugsand other pharmaceutical ingredients which suffer significant loss ofactivity in the lumen of the gastrointestinal tract or in the tissues ofthe gastrointestinal tract during absorption process or upon passagethrough the liver after absorption in the intestinal tract. Absorptionthrough the oral mucosa allows the drug to enter the systemiccirculation without first passing through the liver, and thus alleviatesthe loss of activity upon passage through the liver.

Pharmaceutical ingredients may include, without limitation, analgesics,anti-inflammatories, antipyretics, antibiotics, antimicrobials,laxatives, anorexics, antihistamines, antiasthmatics, antidiuretics,antiflatulents, antimigraine agents, antispasmodics, sedatives,antihyperactives, antihypertensives, tranquilizers, decongestants, betablockers; peptides, proteins, oligonucleotides and other substances ofbiological origin, and combinations thereof. Also encompassed by theterms “active ingredient(s)”, “pharmaceutical ingredient(s)” and “activeagents” are the drugs and pharmaceutically active ingredients describedin Mantelle, U.S. Pat. No. 5,234,957, in columns 18 through 21. Thattext of Mantelle is hereby incorporated by reference. Alternatively oradditionally, the active ingredient can include drugs and otherpharmaceutical ingredients, vitamins, minerals and dietary supplementsas the same are defined in U.S. Pat. No. 5,178,878, the disclosure ofwhich is also incorporated by reference herein.

The dosage form preferably includes an effervescent couple, incombination with the other ingredients to enhance the absorption of thepharmaceutical ingredient across the oral mucosa and to improve thedisintegration profile and the organoleptic properties of the dosageform. For example, the area of contact between the dosage form and theoral mucosa, and the residence time of the dosage form in the oralcavity can be improved by including a bioadhesive polymer in this drugdelivery system. See, e.g., Mechanistic Studies on Effervescent-InducedPermeability Enhancement by Jonathan Eichman (1997), which isincorporated by reference herein. Effervescence, due to its mucusstripping properties, would also enhance the residence time of thebioadhesive, thereby increasing the residence time for the drugabsorption. Non-limiting examples of bioadhesives used in the presentinvention include, for example, Carbopol 934 P, Na CMC, Methocel,Polycarbophil (Noveon AA-1), HPMC, Na alginate, Na Hyaluronate and othernatural or synthetic bioadhesives.

In addition to the effervescence-producing agents, a dosage formaccording to the present invention may also include suitablenon-effervescent disintegration agents. Non-limiting examples ofnon-effervescent disintegration agents include: microcrystalline,cellulose, croscarmellose sodium, crospovidone, starches, corn starch,potato starch and modified starches thereof, sweeteners, clays, such asbentonite, alginates, gums such as agar, guar, locust bean, karaya,pecitin and tragacanth. Disintegrants may comprise up to about 20 weightpercent and preferably between about 2 and about 10% of the total weightof the composition.

In addition to the particles in accordance with the present invention,the dosage forms may also include glidants, lubricants, binders,sweeteners, flavoring and coloring components. Any conventionalsweetener or flavoring component may be used. Combinations ofsweeteners, flavoring components, or sweeteners and flavoring componentsmay likewise be used.

Examples of binders which can be used include acacia, tragacanth,gelatin, starch, cellulose materials such as methyl cellulose and sodiumcarboxy methyl cellulose, alginic acids and salts thereof, magnesiumaluminum silicate, polyethylene glycol, guar gum, polysaccharide acids,bentonites, sugars, invert sugars and the like. Binders may be used inan amount of up to 60 weight percent and preferably about 10 to about 40weight percent of the total composition.

Coloring agents may include titanium dioxide, and dyes suitable for foodsuch as those known as F.D.&C. dyes and natural coloring agents such asgrape skin extract, beet red powder, beta-carotene, annato, carmine,turmeric, paprika, etc. The amount of coloring used may range from about0.1 to about 3.5 weight percent of the total composition.

Flavors incorporated in the composition may be chosen from syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants, leaves, flowers, fruits and so forth and combinations thereof.These may include cinnamon oil, oil of wintergreen, peppermint oils,clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil,oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Alsouseful as flavors are vanilla, citrus oil, including lemon, orange,grape, lime and grapefruit, and fruit essences, including apple, pear,peach, strawberry, raspberry, cherry, plum, pineapple, apricot and soforth. Flavors which have been found to be particularly useful includecommercially available orange, grape, cherry and bubble gum flavors andmixtures thereof. The amount of flavoring may depend on a number offactors, including the organoleptic effect desired. Flavors may bepresent in an amount ranging from about 0.05 to about 3 percent byweight based upon the weight of the composition. Particularly preferredflavors are the grape and cherry flavors and citrus flavors such asorange.

One aspect of the invention provides a solid, oral tablet dosage formsuitable for sublingual, buccal, and gingival administration. Excipientfillers can be used to facilitate tableting. The filler desirably willalso assist in the rapid dissolution of the dosage form in the mouth.Non-limiting examples of suitable fillers include: mannitol, dextrose,lactose, sucrose, and calcium carbonate.

METHOD OF MANUFACTURE

Tablets can either be manufactured by direct compression, wetgranulation or any other tablet manufacturing technique. See, e.g., U.S.Pat. Nos. 5,178,878 and 5,223,264, which are incorporated by referenceherein. The tablet may be a layered tablet consisting of a layer of theactive ingredient sandwiched between a bioadhesive layer and aneffervescence layer. Other layered forms which include the ingredientsset forth above in layers of diverse compositions.

Effervescence Level: Between 5%-95%

Tablet size: Between 3/16″-⅝″

Tablet hardness: Between 5N and 80N

Route of Administration: Sublingual, Buccal, Gingival

The dosage form may be administered to a human or other mammaliansubject by placing the dosage form in the subject's mouth and holding itin the mouth, either adjacent a cheek (for buccal administration),beneath the tongue (for sublingual administration) and between the upperlip and gum (for gingival administration). The dosage form spontaneouslybegins to disintegrate due to the moisture in the mouth. Thedisintegration, and particularly the effervescence, stimulatesadditional salivation which further enhances disintegration.

Example 1

The dosage form should include Fentanyl, an effervescent and pHadjusting substance so that the pH is adjusted to neutral (or slightlyhigher) since the pKa of fentanyl is 7.3. At this pH, the aqueoussolubility of this poorly water-soluble drug would not be compromisedunduly, and would permit a sufficient concentration of the drug to bepresent in the unionized form.

Two fentanyl formulations, each containing 36% effervescence, wereproduced. These tablets were compressed using half-inch shallow concavepunches.

FORMULATION COMPONENT QUANTITY (MG) SHORT Fentanyl, citrate, USP 1.57DISINTEGRATION Lactose monohydrate 119.47 TIME Microcrystalline 119.47Cellulose, Silicified Sodium carbonate, 46.99 anhydrous Sodiumbicarbonate 105 Citric acid, anhydrous 75 Polyvinylphrrolidone, 25cross-linked Magnesium stearate 5 Colloidal silicon dioxide 2.5 Totaltablet mass 500 LONG Fentanyl citrate, USP 1.57 DISINTEGRATION Lactosemonohydrate 270.93 TIME Sodium carbonate, 40.00 anhydrous Sodiumbicarbonate 105 Citric acid, anhydrous 75 Magnesium stearate 5 Colloidalsilicon dioxide 2.5 Total tablet mass 500

Example 2

The dosage form included prochlorperazine (pKa=8.1), an effervescent andpH adjusting substance so that a slightly higher pH is produced tofacilitate the permeation enhancement.

With respect to prochlorperazine, an anti-emetic drug, two formulations,buccal and sublingual, were developed. The buccal tablets werecompressed as quarter inch diameter biconvex tablets, whereas thesublingual tablets were three-eighths inch diameter biconvex tablets.These dimensions were chosen to give a comfortable fit in the respectivepart of the oral cavity for which they were designed. The formulae forthese tablets are as follows:

FORMULATION COMPONENT NAME QUANTITY (MG) BUCCAL Prochlorperazine 5.00Sodium Bicarbonate 15.52 Citric Acid, Anhydrous 11.08 Sodium Bicarbonate45.78 HPMC K4M Prem 5.00 Dicalcium phosphate 5.00 dihydrate Mannitol11.67 Magnesium Stearate 0.95 Total 100.00 SUBLINGUAL Prochlorperazine5.00 Sodium Bicarbonate 61.25 Citric Acid, Anhydrous 43.75 SodiumBicarbonate 95 Sodium carbonate 91.25 HPMC Methocel K4M Prem 40 Mannitol60 Magnesium Stearate 3.75 Total 400

We claim:
 1. A method of manufacturing a compressed tablet suitable fordirect oral administration across the oral mucosa, said methodcomprising the steps of: a) providing an amount of a salt of fentanylthat is pharmaceutically effective for systemic distribution and fororal mucosal administration; b) providing at least one saliva activatedeffervescent couple in an amount that is effective for both tabletdisintegration and an increase in either the rate or extent ofabsorption of said orally administrable medicament across the oralmucosa, wherein said amount of said at least one effervescent coupleranges from about 5% by weight to about 95% by weight; c) producing amixture from said pharmaceutically effective amount of a compositionconsisting of a salt of fentanyl and said saliva activated effervescentcouple; and d) compressing at least a portion of said mixture so as toform at least one tablet.
 2. The method of claim 1, further comprisingthe step of selecting a bioadhesive and producing said mixture includingsame.
 3. The method of claim 1, further comprising the step of:selecting a non-effervescent disintegration agent and producing saidmixture including same.
 4. The method of claim 1, further comprising thestep of: selecting one or more glidants, lubricants, binders,sweeteners, flavoring and coloring components and producing said mixtureincluding same.
 5. The method of claim 1, wherein said at least onesaliva activated effervescent couple is present in an amount betweenabout 20% by weight and 80% by weight.
 6. The method according to claim1, wherein said at least one effervescent couple is present in an amountbetween about 5% by weight to about 80% by weight.
 7. The methodaccording to claim 1, wherein said at least one effervescent couple ispresent in an amount sufficient to evolve a gas in an amount betweenabout 5 cm³ to about 30 cm³.
 8. The method according to claim 1, whereinsaid mixture further comprises a pH adjusting substance.
 9. The methodaccording to claim 8, wherein said pH adjusting substance is a base andsaid base is selected from the group consisting of sodium carbonate,potassium carbonate, magnesium carbonate, disodium hydrogen phosphate,sodium dihydrogen phosphate, dipotassium hydrogen phosphate, andpotassium dihydrogen phosphate.
 10. The method according to claim 1further comprising the step of selecting a pH adjusting substance anddetermining what amount of same is sufficient to change the pH of alocal environment of said tablet at a site of absorption in the mouthand producing said mixture including same.
 11. The method according toclaim 10, wherein said pH adjusting substance is a base.
 12. The methodaccording to claim 11, wherein said base is selected from the groupconsisting of sodium carbonate, potassium carbonate, magnesiumcarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate,dipotassium hydrogen phosphate, and potassium dihydrogen phosphate. 13.A method of manufacturing a tablet suitable for direct oraladministration across the oral mucosa, said method comprising the stepsof: a) selecting at least one orally administrable medicament consistingof a salt of fentanyl, capable of existing in an ionized form and aunionized form in aqueous environment; b) providing a pharmaceuticallyeffective amount for systemic distribution and for oral mucosaladministration of said at least one orally administrable medicament; c)selecting at least one saliva activated effervescent couple; d)selecting a basic pH adjusting substance in an amount sufficient tochange the pH of a local environment of said tablet at a site ofabsorption in the mouth to favor said unionized form of said medicament;e) producing a mixture from said medicament, said selected salivaactivated effervescent couple and said pH adjusting substance, in saidpredetermined amounts; and f) compressing at least a portion of saidmixture so as to form at least one tablet.
 14. The method according toclaim 13, wherein said basic pH adjusting substance is selected from thegroup consisting of sodium carbonate, potassium carbonate, magnesiumcarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate,dipotassium hydrogen phosphate, and potassium dihydrogen phosphate. 15.The method of claim 13 further comprising the step of selecting abioadhesive and producing said mixture including same.
 16. The method ofclaim 13 wherein said amount of said at least one effervescent coupleranges from about 5% by weight to about 80% by weight.
 17. The method ofclaim 13, further comprising the step of: selecting one or moreglidants, lubricants, binders, sweeteners, flavoring and coloringcomponents and producing said mixture including same.
 18. A method ofmanufacturing a tablet suitable for direct oral administration acrossthe oral mucosa, said method comprising the steps of: a) selecting atleast one orally administrable medicament consisting of a salt offentanyl, capable of existing in an ionized form and a unionized form inaqueous environment; b) providing a pharmaceutically effective amountfor systemic distribution and for oral mucosal administration of said atleast one orally administrable medicament; c) selecting at least onesaliva activated effervescent couple in an amount of from about 5% byweight to about 80% by weight; d) selecting a basic pH adjustingsubstance from the group consisting of sodium carbonate, potassiumcarbonate, magnesium carbonate, disodium hydrogen phosphate, sodiumdihydrogen phosphate, dipotassium hydrogen phosphate, and potassiumdihydrogen phosphate, in an amount sufficient to change the pH of alocal environment of said tablet at a site of absorption in the mouth tofavor said unionized form of said medicament; e) selecting a bioadhesivesubstance suitable for use in the oral cavity; f) selecting one or moreexcipient from the group consisting of glidants, lubricants, binders,sweeteners, flavoring and coloring components; g) producing a mixturefrom said medicament, said selected saliva activated effervescentcouple, said pH adjusting substance, said bioadhesive; and saidexcipient; and h) compressing at least a portion of said mixture so asto form at least one tablet.
 19. The tablet produced by the method ofclaim
 1. 20. The tablet produced by the method of claim
 14. 21. Thetablet produced by the method of claim
 15. 22. The tablet produced bythe method of claim
 13. 23. The tablet produced by the method of claim18.
 24. The method of claim 1, wherein the salt of fentanyl comprisesfentanyl citrate.
 25. The method of claim 13, wherein the salt offentanyl comprises fentanyl citrate.
 26. The method of claim 18, whereinthe salt of fentanyl comprises fentanyl citrate.